|Live Attenuated Varicella-Zoster Vaccine: Is It Worth It?|
Live Attenuated Varicella-Zoster Vaccine: Is It Worth It?
Samuel A. Skootsky, M.D.
On May 25, 2006 the Food and Drug Administration (FDA) approved a new live attenuated varicella-zoster vaccine to prevent herpes zoster (shingles) and its complications, most notably post-herpetic neuralgia (PHN). Soon thereafter, on October 26, 2006, the Center for Disease Control & Prevention's Advisory Committee on Immunization Practices (ACIP) recommended this vaccine, Zostavax?, for all adults over 60 years of age.
Zostavax? has been widely promoted, and it has its own website.1 The retail cost is approximately $200. All major insurers, including Medicare Part D plans, now include it in their benefit plans. Because of widespread promotion, older patients often ask about being vaccinated.
Should clinicians encourage patients to get this vaccine? Table 1 shows the results from the clinical trial2 that was used as the basis of the FDA approval and ACIP recommendation. The clinical trial excluded immunocompromised patients and those with a previous episode of herpes zoster. This study reported a relative risk reduction for the incidence of herpes zoster by about 50% overall. The vaccine was 40% less effective in patients aged 70 years or older, possibly due to waning immunolgic response. Therefore, the optimal group to vaccinate may be those 60 to 69 years old.
Although a relative risk reduction of 51.2% is substantial, there are other ways to interpret the data. An alternate measure of efficacy is how many people need to be vaccinated to prevent one additional case of herpes zoster? This number is known as the NNT (number needed to treat). We first need to calculate the absolute risk reduction (ARR). The ARR in this study was 5.7 cases per 1000 person years (from Table 1: placebo incidence 11.12 less vaccine incidence 5.42) or 0.57%. Simply put, the NNT is equal to 1/ARR. For this vaccine study, the NNT is 175. In other words, one case of herpes zoster was avoided for every 175 people vaccinated.
A similar analysis for patients aged 70 years or older shows that 231 people need to be vaccinate to prevent one episode of herpes zoster. The higher NNT in this age group is higher than for the study as a whole, due to reduced efficacy.
To put these results into perspective, a large clinical trial of influenza vaccination in patients aged 60 years or older3 the NNT (to prevent influenza seroconversion) was 20.
What complications are due to this vaccine? There were no increases in deaths or hospitalizations from any cause reported.2 But risk of adverse events at the injection site was significant: 48% in the vaccine group versus 17% in the placebo group. This is an absolute risk increase (ARI) of 31%. This can be related to the idea of a number needed to harm, or NNH, which is equal to 1/ARI. In this example, the NNH is about 3, which means that one patient will have an adverse reaction at the injection site for every 3 vaccinated. Because it is a live vaccine, it is contraindicated in immunocompromised states. It is also contraindicated in those allergic to gelatin and neomycin, which are components of the vaccine as distributed by Merck.
How does the vaccine affect PHN? This is the most commonly feared complication of the disease itself. The lifetime risk of herpes zoster for a person aged 60 years or older is approximately 18%,4 and about 25% will experience PHN. In some patients, the pain may last a year or more. Post-herpetic neuralgia is associated with reduced quality of life, may persist for years, is often refractory to treatment, and is not prevented by anti-viral treatment.2 The prevalence of PHN increases with age (see Table 2).
The vaccine trial reported an impressive relative risk reduction of 66% in the incidence of PHN (Table 2). Vaccine efficacy in preventing PHN was no less effective in patients aged 70 years or older. Considering that the vaccine was less effective in older age groups in preventing shingles, the data on PHN prevention suggest that the vaccine is relatively more effective in older age groups in preventing PHN.
The AAR for PHN in this study was 0.92 cases per 1000 person years (1.38-0.46) or .092%. How many people need to be vaccinated to prevent one case of PHN? Again, NNT is equal to 1/ARR. For theprevention of PHN, the NNT is 1087. This means that one case of herpes zoster will be avoided for every 1087 people vaccinated.
A similar analysis shows that 704 people need to be vaccinate to prevent one episode in the group aged 70years or older.
The major uncertainty in the use of this vaccine relates to the long-term efficacy of vaccination. In a recent article that used a computer simulation to model vaccinated and placebo cohorts, both the longterm efficacy and the cost of the vaccine would greatly alter the "cost effectiveness" of the vaccination. In short, at a cost of less than $200, the vaccine was deemed cost effective using a quality-adjusted life-year (QALY) analysis, but only if the vaccine was effective for 30 years.5 Quality-adjusted life-year analysis has more to do with population-based management than individual patients. Because insurance plans, including the government sponsored Part D plans, do cover this vaccine in spite of the uncertainties, implies that a "willingness to pay" determination has been made due to perceived diseaseburden, lack of serious side effects, and patient interest.6
An important practical issue is that current varicellazoster vaccines require frozen storage (-15ºC or 5ºF). The frozen vaccine must be reconstituted and administered within 30 minutes. Reconstituted vaccine cannot be stored. It is not known to what extent physician offices and pharmacies have the proper storage capabilities. To avoid storage issues, many physicians give the patient a prescription for the vaccine that they then bring back to the physician'soffice for administration. But this may be a disservice to the patient. Merck does not recommend any transportationof vaccine to another site for administration unless frozen conditions are maintained.7 They do offer advice on an ad hoc basis about potency of a particular single dose if you give them the lot number, expiration date, temperature and number of hours of exposure to non-frozen conditions. No information will be given for exposure to temperatures above 77?F.7
My conclusions and important observations from the material presented above are as follows:
Submitted on November 17, 2006